Abstract
Pregnanolone glutamate (PA-G) is a neuroactive steroid that has been previously demonstrated to be a potent neuroprotective compound in several biological models in vivo. Our in vitro experiments identified PA-G as an inhibitor of N-methyl-D-aspartate receptors and a potentiator of γ-aminobutyric acid receptors (GABAARs). In this study, we addressed the hypothesis that combined GABAAR potentiation and NMDAR antagonism could afford a potent anticonvulsant effect. Our results demonstrated the strong age-related anticonvulsive effect of PA-G in a model of pentylenetetrazol-induced seizures. PA-G significantly decreased seizure severity in 12-day-old animals, but only after the highest dose in 25-day-old animals. Interestingly, the anticonvulsant effect of PA-G differed both qualitatively and quantitatively from that of zuranolone, an investigational neurosteroid acting as a potent positive allosteric modulator of GABAARs. Next, we identified 17-hydroxy-pregnanolone (17-OH-PA) as a major metabolite of PA-G in 12-day-old animals. Finally, the administration of PA-G demonstrated direct modulation of unexpected neurosteroid levels, namely pregnenolone and dehydroepiandrosterone sulfate. These results suggest that compound PA-G might be a pro-drug of 17-OH-PA, a neurosteroid with a promising neuroprotective effect with an unknown mechanism of action that may represent an attractive target for studying perinatal neural diseases.
Highlights
Introduction published maps and institutional affilNeurosteroids (NS) are synthesized de novo in the brain and modulate the receptors for neurotransmitters, especially glutamate and γ-aminobutyric acid (GABAA R)
The anticonvulsant effect of the compounds pregnanolone sulfate (PA-S) and pregnanolone glutamate (PA-G) are summarized in Figures 2 and 3, respectively
At a dose of 100 mg/kg resulted in the development of generalized seizures (GS) in all vehicle-treated animals, and complete generalized tonic-clonic seizures (GTCS) with a tonic phase (TP) were observed in six out of eight animals
Summary
Neurosteroids (NS) are synthesized de novo in the brain and modulate the receptors for neurotransmitters, especially glutamate and γ-aminobutyric acid (GABAA R). NS and their synthetic analogs, neuroactive steroids (NAS), readily cross the blood–brain barrier. The unconjugated structures are transported passively due to their lipophilic structure, while the conjugated steroids (e.g., sulfates) are dependent on selective uptake or efflux proteins [1,2,3]. NS and NAS modulate many functions of the central and peripheral nervous system, including development and other complex behavior [4]. The synaptic receptors for γ-aminobutyric acid (GABAA Rs) expressed in murine cortical pyramidal neurons and interneurons during early neonatal development (P7–15) are influenced by an endogenous NS tone. The findings of neurosteroids’ influence on brain-region-dependent neurotransmission [5,8,9] suggest iations
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